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1.
Blood ; 140(12): 1408-1418, 2022 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-35667047

RESUMO

To determine the survival benefit of allogeneic hematopoietic cell transplantation (allo-HCT) in chronic myelomonocytic leukemias (CMML), we assembled a retrospective cohort of CMML patients 18-70 years old diagnosed between 2000 and 2014 from an international CMML dataset (n = 730) and the EBMT registry (n = 384). The prognostic impact of allo-HCT was analyzed through univariable and multivariable time-dependent models and with a multistate model, accounting for age, sex, CMML prognostic scoring system (low or intermediate-1 grouped as lower-risk, intermediate-2 or high as higher-risk) at diagnosis, and AML transformation. In univariable analysis, lower-risk CMMLs had a 5-year overall survival (OS) of 20% with allo-HCT vs 42% without allo-HCT (P < .001). In higher-risk patients, 5-year OS was 27% with allo-HCT vs 15% without allo-HCT (P = .13). With multistate models, performing allo-HCT before AML transformation reduced OS in patients with lower-risk CMML, and a survival benefit was predicted for men with higher-risk CMML. In a multivariable analysis of lower-risk patients, performing allo-HCT before transformation to AML significantly increased the risk of death within 2 years of transplantation (hazard ratio [HR], 3.19; P < .001), with no significant change in long-term survival beyond this time point (HR, 0.98; P = .92). In higher-risk patients, allo-HCT significantly increased the risk of death in the first 2 years after transplant (HR 1.46; P = .01) but not beyond (HR, 0.60; P = .09). Performing allo-HCT before AML transformation decreases life expectancy in lower-risk patients but may be considered in higher-risk patients.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mielomonocítica Crônica , Leucemia Mielomonocítica Juvenil , Adolescente , Adulto , Idoso , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucemia Mielomonocítica Crônica/diagnóstico , Leucemia Mielomonocítica Crônica/terapia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplante Homólogo , Adulto Jovem
2.
Br J Haematol ; 149(3): 376-82, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20230405

RESUMO

This study compared two schedules of low-dose gemtuzumab ozogamicin (GO) as induction monotherapy for untreated acute myeloid leukaemia in older patients unfit for intensive chemotherapy, to identify the more promising regimen for further study. Patients were randomized to receive either best supportive care or a course of GO according to one of two schedules: 3 mg/m(2) on days 1, 3 and 5 (arm A), or GO 6 mg/m(2) on day 1 and 3 mg/m(2) on day 8 (arm B). Primary endpoint was the rate of disease non-progression (DnP), defined as the proportion of patients either achieving a response or maintaining a stable disease following GO induction in each arm. Fifty-six patients were randomized in the two GO arms (A, n = 29; B, n = 27). The rate of DnP was 38% [90% confidence interval (CI), 23-55] in arm A, and 63% (90% CI, 45-78) in arm B. Peripheral cytopenias were the most common adverse events for both regimens. The all-cause early mortality rate was 14% in arm A and 11% in arm B. The day 1 + 8 schedule, which was associated with the highest rate of DnP, met the statistical criteria to be selected as the preferred regimen for phase III comparison with best supportive care.


Assuntos
Aminoglicosídeos/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Idoso , Aminoglicosídeos/efeitos adversos , Aminoglicosídeos/uso terapêutico , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Progressão da Doença , Esquema de Medicação , Estudos de Viabilidade , Feminino , Gemtuzumab , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
3.
Blood ; 112(3): 750-9, 2008 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-18474725

RESUMO

The interleukin-12 (IL-12) receptor (R) B2 gene acts as tumor suppressor in human acute and chronic B-cell leukemias/lymphomas and IL-12rb2-deficient mice develop spontaneously localized plasmacytomas. With this background, we investigated the role of IL-12R beta 2 in multiple myeloma (MM) pathogenesis. Here we show the following: (1) IL-12R beta 2 was expressed in primary MM cells but down-regulated compared with normal polyclonal plasmablastic cells and plasma cells (PCs). IL-6 dampened IL-12R beta 2 expression on polyclonal plasmablastic cells and MM cells. (2) IL-12 reduced the proangiogenic activity of primary MM cells in vitro and decreased significantly (P = .001) the tumorigenicity of the NCI-H929 cell line in SCID/NOD mice by inhibiting cell proliferation and angiogenesis. The latter phenomenon was found to depend on abolished expression of a wide panel of proangiogenic genes and up-regulated expression of the antiangiogenic genes IFN-gamma, IFN-alpha, platelet factor-4, and TIMP-2. Inhibition of the angiogenic potential of primary MM cells was related to down-regulated expression of the proangiogenic genes CCL11, vascular endothelial-cadherin, CD13, and AKT and to up-regulation of an IFN-gamma-related antiangiogenic pathway. Thus, IL-12R beta 2 directly restrains MM cell growth, and targeting of IL-12 to tumor cells holds promise as new therapeutic strategy.


Assuntos
Regulação Neoplásica da Expressão Gênica , Mieloma Múltiplo/química , Receptores de Interleucina-12/análise , Idoso , Idoso de 80 Anos ou mais , Animais , Proliferação de Células/efeitos dos fármacos , Humanos , Interleucina-12/farmacologia , Camundongos , Camundongos SCID , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/genética , Receptores de Interleucina-12/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Blood ; 112(6): 2450-62, 2008 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-18583568

RESUMO

We demonstrate that blockade of the MEK/ERK signaling module, using the small-molecule inhibitors PD184352 or PD325901 (PD), strikingly enhances arsenic trioxide (ATO)-induced cytotoxicity in human myeloma cell lines (HMCLs) and in tumor cells from patients with multiple myeloma (MM) through a caspase-dependent mechanism. In HMCLs retaining a functional p53, PD treatment greatly enhances the ATO-induced p53 accumulation and p73, a p53 paralog, cooperates with p53 in caspase activation and apoptosis induction. In HMCLs carrying a nonfunctional p53, cotreatment with PD strikingly elevates the (DR4 + DR5)/(DcR1 + DcR2) tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptors ratio and caspase-8 activation of ATO-treated cells. In MM cells, irrespective of p53 status, the combined PD/ATO treatment increases the level of the proapoptotic protein Bim (PD-mediated) and decreases antiapoptotic protein Mcl-1 (ATO-mediated). Moreover, Bim physically interacts with both DR4 and DR5 TRAIL receptors in PD/ATO-treated cells, and loss of Bim interferes with the activation of both extrinsic and intrinsic apoptotic pathways in response to PD/ATO. Finally, PD/ATO treatment induces tumor regression, prolongs survival, and is well tolerated in vivo in a human plasmacytoma xenograft model. These preclinical studies provide the framework for testing PD325901 and ATO combination therapy in clinical trials aimed to improve patient outcome in MM.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Arsenicais/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mieloma Múltiplo/tratamento farmacológico , Óxidos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Trióxido de Arsênio , Arsenicais/uso terapêutico , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Difenilamina/análogos & derivados , Difenilamina/farmacologia , Difenilamina/uso terapêutico , Humanos , Camundongos , Camundongos SCID , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Mieloma Múltiplo/patologia , Óxidos/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
5.
J Cell Physiol ; 220(2): 401-9, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19365806

RESUMO

Bone marrow stromal cells (MSCs) and osteoblasts are the two main non-haematopoietic cellular components of human bone tissue. To identify novel osteoblast-related molecules, we performed a gene expression profiling analysis comparing MSCs and osteoblasts isolated from the same donors. Genes differentially overexpressed in osteoblasts were mainly related to the negative control of cell proliferation, pro-apoptotic processes, protein metabolism and bone remodelling. Notably, we also identified the collagen XV (COL15A1) gene as the most up-regulated gene in osteoblasts compared with MSCs, previously described as being expressed in the basement membrane in other cell types. The expression of collagen type XV was confirmed at the protein level on isolated osteoblasts and we demonstrated that it significantly increases during the osteogenic differentiation of MSCs in vitro and that free ionised extracellular calcium significantly down-modulates its expression. Moreover, light and electron microscopy showed that collagen type XV is expressed in bone tissue biopsies mainly by working osteoblasts forming new bone tissue or lining bone trabeculae. To our knowledge, these data represent the first evidence of the expression of collagen type XV in human osteoblasts, a calcium-regulated protein which correlates to a specific functional state of these cells.


Assuntos
Colágeno/metabolismo , Matriz Extracelular/metabolismo , Perfilação da Expressão Gênica , Análise em Microsséries , Osteoblastos/metabolismo , Idoso , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Cálcio/metabolismo , Diferenciação Celular/fisiologia , Proliferação de Células , Células Cultivadas , Colágeno/genética , Matriz Extracelular/química , Humanos , Pessoa de Meia-Idade , Osteoblastos/citologia , Osteogênese/fisiologia , Fenótipo , Células Estromais/citologia , Células Estromais/metabolismo
6.
Haematologica ; 94(1): 87-93, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19001278

RESUMO

BACKGROUND: XIAP is the best characterized and the most potent direct endogenous caspase inhibitor and is considered a key actor in the control of apoptotic threshold in cancer cells. In this report, we specifically addressed XIAP regulation and function in myeloma cells. DESIGN AND METHODS: XIAP and its endogenous inhibitor XAF-1 protein levels and their regulation were assessed by immunoblot analysis in myeloma cell lines or primary myeloma cells. XIAP knockdown by RNA interference was used to evaluate XIAP impact on in vitro drug sensitivity and in vivo tumor growth. RESULTS: Our results indicate that myeloma cells expressed high levels of XIAP protein that were tightly regulated during growth factor stimulation or stress condition. Of note, an increased XIAPlevel was evidenced during the blockade of the canonical cap-dependent translation by the mTOR inhibitor rapamycin, supporting the hypothesis of a functional IRES sequence in XIAP mRNA. In addition, caspase-mediated XIAP cleavage correlated to an apoptotic process occurring upon cell treatment with the proteasome inhibitor bortezomib. Importantly, XIAP knockdown using RNA interference enhanced drug sensitivity and decreased tumor formation in NOD/SCID mice. Finally, myeloma cells also expressed the XIAP inhibitor XAF-1 that interacted with XIAP in viable myeloma cells. CONCLUSIONS: Altogether, our data argue for a delicate control of XIAP function in myeloma cells and stimulate interest in targeting XIAP in myeloma treatment.


Assuntos
Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Camundongos Nus , Camundongos SCID , Mieloma Múltiplo/genética , Interferência de RNA , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Cancer Res ; 67(16): 7665-74, 2007 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-17702698

RESUMO

Osteoblast impairment occurs within multiple myeloma cell infiltration into the bone marrow. Canonical Wnt signaling activation in osteoprogenitor cells is involved in osteoblast formation through the stabilization of dephosphorylated beta-catenin and its nuclear translocation. The effects of multiple myeloma cells on Wnt signaling in human mesenchymal/osteoprogenitor cells are unclear. In 60 multiple myeloma patients checked, we found that among the Wnt inhibitors, Dickkopf-1 and secreted frizzled-related protein-3 were produced by multiple myeloma cells. However, although multiple myeloma cells or multiple myeloma bone marrow plasma affected expression of genes in the canonical Wnt signaling and inhibited beta-catenin stabilization in murine osteoprogenitor cells, they failed to block the canonical Wnt pathway in human mesenchymal or osteoprogenitor cells. Consistently, Wnt3a stimulation in human osteoprogenitor cells did not blunt the inhibitory effect of multiple myeloma cells on osteoblast formation. Consequently, despite the higher Wnt antagonist bone marrow levels in osteolytic multiple myeloma patients compared with nonosteolytic ones, beta-catenin immunostaining was not significantly different. Our results support the link between the production of Wnt antagonists by multiple myeloma cells and the presence of bone lesions in multiple myeloma patients but show that myeloma cells do not inhibit canonical Wnt signaling in human bone microenvironment.


Assuntos
Células da Medula Óssea/metabolismo , Glicoproteínas/biossíntese , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Mieloma Múltiplo/metabolismo , Proteínas Wnt/antagonistas & inibidores , Animais , Células da Medula Óssea/patologia , Linhagem Celular Tumoral , Técnicas de Cocultura , Glicoproteínas/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Osteoblastos/metabolismo , Osteoblastos/patologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Transdução de Sinais , Células-Tronco/metabolismo , Células-Tronco/patologia , Proteínas Wnt/metabolismo
8.
Leuk Res ; 32(1): 49-53, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17512053

RESUMO

This study examines the response to dexamethasone-doxorubicin-vincristine (DAV) therapy, followed by conditioning regimen and autologous stem cells transplantation (ASCT) in patients with multiple myeloma in relation with the presence of polymorphisms in genes involved in drug metabolism (GSTP1) and DNA synthesis (TYMS). GSTP1 G313G genotype (OR=5.49; 95% CI, 1.3-22.5, p=0.02) and TYMS A227A genotype (OR=3.41; 95% CI, 1.3-8.9, p=0.01) resulted significantly associated with a poor response following chemotherapy and the risk increased for the combined genotype (OR=13.54; 95% CI, 2.0-91.3, p=0.01). TYMS T157T genotype was significantly associated with a poor response after ASCT (OR=4.60; 95% CI, 1.2-16.9, p=0.02). Pre-therapeutic individual determination of the GSTP1 and TYMS polymorphisms could help in choosing the most appropriate protocol.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Glutationa S-Transferase pi/genética , Mieloma Múltiplo/genética , Mieloma Múltiplo/terapia , Polimorfismo de Nucleotídeo Único , Transplante de Células-Tronco , Timidilato Sintase/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Ciclofosfamida/uso terapêutico , Dacarbazina/uso terapêutico , Feminino , Humanos , Masculino , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Nimustina/uso terapêutico , Análise de Sobrevida , Condicionamento Pré-Transplante , Transplante Autólogo , Resultado do Tratamento , Vincristina/uso terapêutico
9.
Leuk Lymphoma ; 48(12): 2323-9, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18067006

RESUMO

Bone destruction is the hallmark of multiple myeloma (MM) due to the high capacity of malignant plasma cells to induce a severe imbalance of bone remodeling. Growing evidences suggest that MM cell interactions with bone marrow (BM) osteoblast have a critical role in the pathophysiology of osteolytic lesions. Indeed histomorphometric studies have demonstrated that MM patients with osteolytic bone lesions have lower numbers of osteoblasts and decreased bone formation together with osteoclast activation. Recently, the biological mechanisms involved in the osteoblast inhibition induced by MM cells have begun to be elucidated, underlying the main role of the block of osteoblast differentiation in the development of bone lesions. In this article, we summarize the main mechanisms regulating MM cell and osteoblast interactions.


Assuntos
Células da Medula Óssea/fisiologia , Comunicação Celular , Mieloma Múltiplo/patologia , Osteoblastos/fisiologia , Osteólise/etiologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Interleucina-3/fisiologia , Interleucina-7/fisiologia , Complexo de Endopeptidases do Proteassoma/fisiologia , Ubiquitina/metabolismo , Proteínas Wnt/fisiologia
10.
Tumori ; 93(1): 97-9, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17455879

RESUMO

Most of the information about the genetic composition of parathyroid tumors has been obtained by comparative genomic hybridization (CGH) and loss of heterozygosity (LOH) studies, whereas only few conventional cytogenetic investigation results are available. We have performed cytogenetic analysis of short-term cultures from 3 parathyroid adenoma tissue samples. Two cases showed a normal karyotype in all the metaphases obtained from independent primary cultures. In one case 5 metaphases (in a total of 25) from 2 independent cultures showed a nonrandom translocation t(4;13)(q21;q14), which was therefore accepted as clonal. To our knowledge this is the second clonal translocation described in this tumor type. Further conventional cytogenetic analysis of more parathyroid tumor specimens would be necessary to identify other specific abnormalities and the involved genes with a potential important role in the diagnosis, prognosis and pathogenesis of parathyroid tumors.


Assuntos
Adenoma/genética , Aberrações Cromossômicas , Cromossomos Humanos Par 13/genética , Cromossomos Humanos Par 4/genética , Neoplasias das Paratireoides/genética , Translocação Genética , Análise Citogenética , Humanos , Cariotipagem
11.
Haematologica ; 91(11): 1489-97, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17082008

RESUMO

BACKGROUND AND OBJECTIVES: The chemokine receptor CXCR3, involved in chemotaxis, is expressed on normal and malignant B cells and plasma cells. Recent data suggest that CXCR3-binding chemokines may also regulate proliferation and survival in endothelial cells through the interaction with two distinct isoforms of CXCR3 (CXCR3-A and CXCR3-B). DESIGN AND METHODS: We evaluated the potential expression of CXCR3 isoforms in myeloma cells, also investigating whether CXCR3 expression is affected by cell cycle and apoptosis. Furthermore, we assessed the effect of CXCR3 activation on myeloma cell proliferation and survival. RESULTS: We found that CXCR3 is widely expressed on human myeloma cell lines and freshly purified myeloma cells. The presence of both CXCR3 isoforms, CXCR3-A and CXCR3-B, was observed in myeloma cells with different ratios of expression. Interestingly, we found that CXCR3 expression in myeloma cell was cell cycle dependent and that myeloma growth factors inhibited CXCR3 expression in myeloma cells. On the other hand, we found that FAS (CD95)-mediated apoptosis up-regulated CXCR3 expression. A similar behavior was observed for the CXCR3-binding chemokines. Finally we found that the activation of CXCR3 on myeloma cells by CXCL10/IP-10 partially blunted FAS-mediated apoptosis in myeloma cells that express CXCR3-A and that high concentrations of CXCL10/IP-10 inhibit myeloma cell proliferation. INTERPRETATION AND CONCLUSIONS Our data indicate that myeloma cells express the CXCR3 system with patterns correlated to cell cycle and apoptosis and that CXCR3 activation may affect myeloma cell survival and proliferation.


Assuntos
Proliferação de Células , Quimiocinas/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Receptores de Quimiocinas/biossíntese , Linhagem Celular Tumoral , Sobrevivência Celular/fisiologia , Quimiocinas/biossíntese , Quimiocinas/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Mieloma Múltiplo/genética , Ligação Proteica/fisiologia , Isoformas de Proteínas/biossíntese , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores CXCR3 , Receptores de Quimiocinas/genética
12.
Haematologica ; 90(2): 275-8, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15710592

RESUMO

The direct expression and production of the critical osteoclastogenic factor, the receptor activator of NF-kB ligand (RANKL), is a matter of controversy. In this study we definitively demonstrate by both qualitative and quantitative polymerase chain reaction analysis that human myeloma cells do not express significant levels of RANKL mRNA or produce RANKL able to stimulate osteoclast formation.


Assuntos
Proteínas de Transporte/metabolismo , Proteínas de Transporte/fisiologia , Regulação Neoplásica da Expressão Gênica , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/fisiologia , Mieloma Múltiplo/metabolismo , Linhagem Celular Tumoral , Citometria de Fluxo , Humanos , Osteoclastos/metabolismo , Isoformas de Proteínas , Ligante RANK , RNA Mensageiro/metabolismo , Receptor Ativador de Fator Nuclear kappa-B , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Regulação para Cima
13.
Leuk Lymphoma ; 46(1): 29-33, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15621778

RESUMO

Multiple myeloma (MM) is a plasma cell malignancy characterized by an increase of the bone marrow angiogenesis. Angiopoietin-1 (Ang-1) is a critical factor in the regulation of physiological and pathological vessel formation that acts by binding to a specific receptor Tie2 expressed on endothelial cells. Recent evidences indicate that human MM cells produce Ang-1 and up-regulate its receptor Tie2 in bone marrow endothelial cells. An overexpression of Ang-1 has been also found in MM cells as compared to normal plasma cells. The correlation between Ang-1 expression and BM angiogenesis, demonstrated in MM patients, and the inhibitory effect of Tie2 blocking on MM-induced vessel formation suggest that Ang-1 production by MM cells is critically involved in the angiogenic process in MM. In this review we focalize our attention on Ang-1/Tie2 system and its role in MM-induced angiogenesis.


Assuntos
Angiopoietina-1/metabolismo , Mieloma Múltiplo/fisiopatologia , Neovascularização Patológica , Humanos , Mieloma Múltiplo/patologia , Transdução de Sinais , Células Estromais/metabolismo
14.
Exp Hematol ; 32(8): 685-91, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15308315

RESUMO

The increase of osteoclast activation and formation is mainly involved in the development of the osteolytic bone lesions that characterize multiple myeloma (MM) patients. The mechanisms by which myeloma cells induce bone resorption have not been clear for many years. Recently, new evidence has elucidated which factors are critically involved in the activation of osteoclastic cells in MM. The potential role of the critical osteoclastogenic factor, the receptor activator of NF-kappaB ligand (RANKL), and its soluble antagonist osteoprotegerin (OPG) in the activation of bone resorption in MM is summarized in this review. It has been demonstrated that human MM cells induce an imbalance in the bone marrow environment of the RANKL/OPG ratio in favor of RANKL that triggers the osteoclast formation and activation leading to bone destruction. The direct production of the chemokine macrophage inflammatory protein-1 alpha (MIP-1alpha) by myeloma cells, in combination with the RANKL induction in BM stromal cells in response to myeloma cells, are critical in osteoclast activation and osteoclastogenesis.


Assuntos
Reabsorção Óssea/etiologia , Proteínas de Transporte/fisiologia , Glicoproteínas de Membrana/fisiologia , Mieloma Múltiplo/complicações , Osteoclastos/fisiologia , Animais , Quimiocina CCL3 , Quimiocina CCL4 , Modelos Animais de Doenças , Glicoproteínas/fisiologia , Humanos , Interleucina-7/fisiologia , Proteínas Inflamatórias de Macrófagos/fisiologia , Osteoprotegerina , Ligante RANK , Receptor Ativador de Fator Nuclear kappa-B , Receptores Citoplasmáticos e Nucleares/fisiologia , Receptores do Fator de Necrose Tumoral , Células Estromais/fisiologia
15.
Biochem Pharmacol ; 63(5): 967-75, 2002 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-11911849

RESUMO

Recent advances in chemotherapy have focused on the benefit of high dose regimens, increasing the dose intensity of conventional chemotherapy. However, unacceptable cytotoxicity and genotoxicity on normal cells often impairs the proper management of patients. Phosphoaminothiol WR-1065, the active metabolite of amifostine, appears to protect normal cells and tissues against cytotoxic exposure to radiation or chemotherapeutic agents. Nevertheless, there is disagreement in findings on amifostine protection against bleomycin-induced severe side effects which have suggested that amifostine effectiveness against bleomycin-induced genotoxicity in normal leukocytes and tumour line cells K562 be studied. DNA damage was detected by single cell gel electrophoresis (or Comet) assay, a technique able to detect DNA strand breaks, alkali-labile sites and incomplete excision repair events in individual cells and which appears to be an ideal tool for assessing variability in response of different cell types in vitro. WR-2721 appears to selectively protect healthy leukocytes but not K562 tumoral cells. On the other hand, data on the inter- and intra-individual sensitivity to bleomycin and amifostine suggest that individual metabolic/genetic differences and other factors relating to lifestyle may be responsible for response variability. Application of the Comet assay in appropriate clinical settings to test the sensitivity of patients when undergoing chemotherapy appears possible.


Assuntos
Amifostina/farmacologia , Bleomicina/farmacologia , Dano ao DNA , Leucócitos/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Antimetabólitos Antineoplásicos/farmacologia , Interações Medicamentosas , Humanos , Células K562/efeitos dos fármacos , Testes de Mutagenicidade
16.
Haematologica ; 89(9): 1118-23, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15377473

RESUMO

BACKGROUND AND OBJECTIVES: The receptor activator of NF-kB ligand (RANKL) has a critical role in osteoclast activation. Recently it has been demonstrated that human multiple myeloma (MM) cells do not express RANKL but up-regulate RANKL in bone marrow stromal cells (BMSC). To further investigate the role of RANKL in the pathophysiology of MM we evaluated the expression of its receptor RANK in MM cells and in the BM environment and the potential role of RANKL in the interaction of myeloma cells with the microenvironment. DESIGN AND METHODS: RANK mRNA and protein expression were evaluated by reverse transcription polymerase chain reaction and Western blot analysis in human myeloma cell lines (HMCL), fresh purified MM cells, BMSC and endothelial cells. Moreover the effect and the role of RANKL on cytokine secretion were evaluated in BMSC, in endothelial cells and in co-culture conditions with myeloma cells. RESULTS: We found that RANK is expressed in BMSC and endothelial cells but not in myeloma cells. Consistently, RANKL did not have a direct effect on myeloma cell survival, but RANKL treatment induced a significant increase of interleukin (IL)-6 and IL-11 secretion by both BMSC and endothelial cells. Moreover, in a co-culture system we found that myeloma cells up-regulated both IL-6 and IL-11 secretion by BMSC and endothelial cells through cell-to-cell contact. The presence of the RANK-Fc that blocks the RANK/RANKL interaction significantly inhibited HMCL-induced secretion of IL-6 and IL-11. INTERPRETATION AND CONCLUSIONS: Our data provide new notions on the role of the RANKL system in the pathophysiology of MM.


Assuntos
Proteínas de Transporte/fisiologia , Interleucina-11/metabolismo , Interleucina-6/metabolismo , Glicoproteínas de Membrana/fisiologia , Mieloma Múltiplo/fisiopatologia , Medula Óssea/metabolismo , Medula Óssea/patologia , Proteínas de Transporte/biossíntese , Proteínas de Transporte/genética , Comunicação Celular , Técnicas de Cocultura , Células Endoteliais/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Fragmentos Fc das Imunoglobulinas/farmacologia , Interleucina-11/biossíntese , Interleucina-11/genética , Interleucina-6/biossíntese , Interleucina-6/genética , Glicoproteínas de Membrana/biossíntese , Glicoproteínas de Membrana/genética , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Osteoclastos/metabolismo , Ligante RANK , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Receptor Ativador de Fator Nuclear kappa-B , Células Estromais/metabolismo , Células Tumorais Cultivadas/metabolismo , Regulação para Cima
17.
Leuk Lymphoma ; 45(6): 1141-7, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15359993

RESUMO

The aim of the study was to determine the safety and efficacy of the combination of fludarabine (FLU), cyclophosphamide (CY) and mitoxantrone (FLU/CY/MITO) in untreated follicular lymphomas (FL), Sixty patients with newly diagnosed stage II bulky to IV FL, median age 59 years (range 36-70), received FLU/CY/MITO regimen (FLU 25 mg/m2 days 1-3, CY 300 mg/m2 days 1-3, Mito 10 mg/m2 day 1). Patients received antibiotic oral prophylaxis during all treatments, and growth factors (G-CSF) when grade III granulocytopenia (WHO) occurred. The overall response rate was 87%: 46 patients achieved complete response (CR) (77%), 6 a partial response (10%) and 8 were non-responders. Fifty patients are surviving with a median observation time of 31 months. The 4-year estimated probability of overall survival and failure-free survival were 78.2% and 45% respectively. Thirty-five patients (58%) are still in CR. Sixty percent of patients experienced grade III-IV granulocytopenia. Two patients suffered grade III pulmonary infection and one grade III liver toxicity. In a subset of 46 patients, bcl-2 translocation was positive in bone marrow (BM) and/or peripheral blood (PB) of 36 patients. At the end of treatment, 25 of these patients had CR and 19 (76%) converted to polymerase chain reaction (PCR) negativity. FLU/CY/MITO regimen showed a high level of activity in follicular lymphoma. Toxicity, mainly hematological, was acceptable and the treatment was made feasible by the use of antibiotic prophylaxis and G-CSF. Significant non-hematological toxicities were seen, but no patients died. The conversion of bcl-2 from positive to negative by PCR in BM and/or PB suggests a possible role for this treatment in clearing minimal residual disease and improving patients' outcome.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Folicular/tratamento farmacológico , Vidarabina/análogos & derivados , Adulto , Idoso , Medula Óssea , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Linfoma Folicular/mortalidade , Masculino , Pessoa de Meia-Idade , Mitoxantrona/administração & dosagem , Neoplasia Residual/tratamento farmacológico , Transporte Proteico , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Segurança , Taxa de Sobrevida , Resultado do Tratamento , Vidarabina/administração & dosagem
18.
Acta Biomed ; 75(3): 143-52, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15796087

RESUMO

Multiple myeloma (MM) is a plasma cell malignancy characterized by the high capacity to induce osteolytic bone lesions that mainly result from an increased bone resorption related to the stimulation of osteoclast recruitment and activity. Although it is known that myeloma cells induce osteoclastic bone resorption, the biological mechanisms involved in the pathophysiology of MM-induced bone resorption have been unclear for several years. Recently, new data seem to elucidate which mechanism is critically involved in the activation of osteoclastic cells in MM. The critical osteoclastogenetic factor RANKL and its soluble antagonist osteoprotegerin (OPG) are the major candidates in the pathophysiology of MM bone disease. Human MM cells induce an imbalance in the RANKL/OPG ratio in the bone marrow environment that triggers the osteoclast formation and activation leading to bone destruction. The role or RANKL/OPG system and other osteoclast stimulating factors in the pathophysiology of MM bone disease are summarized in this update.


Assuntos
Mieloma Múltiplo/complicações , Osteólise/etiologia , Animais , Medula Óssea/metabolismo , Reabsorção Óssea/etiologia , Reabsorção Óssea/fisiopatologia , Proteínas de Transporte/fisiologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral/metabolismo , Quimiocina CCL4 , Meios de Cultivo Condicionados/farmacologia , Citocinas/fisiologia , Glicoproteínas/fisiologia , Humanos , Interleucina-6/fisiologia , Interleucina-7/fisiologia , Proteínas Inflamatórias de Macrófagos/fisiologia , Glicoproteínas de Membrana/fisiologia , Camundongos , Mieloma Múltiplo/fisiopatologia , Proteínas de Neoplasias/fisiologia , Osteoblastos/fisiologia , Osteoclastos/metabolismo , Osteoclastos/patologia , Osteoprotegerina , Ligante RANK , Receptor Ativador de Fator Nuclear kappa-B , Receptores Citoplasmáticos e Nucleares/fisiologia , Receptores do Fator de Necrose Tumoral , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Células Estromais/patologia , Subpopulações de Linfócitos T/metabolismo
19.
Exp Hematol ; 41(4): 387-97.e1, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23178378

RESUMO

Multiple myeloma (MM)-induced osteoclast (OC) formation is mainly due to an imbalance of the receptor activator NF-κB ligand (RANKL)-osteoprotegerin (OPG) ratio in favor of RANKL in the bone microenvironment and to the CCL3 production by MM cells. The purpose of the study was to investigate the effect of the immunomodulatory drugs on RANKL/OPG ratio, the production of pro-osteoclastogenic cytokines, and MM-induced OC formation. We found that in vivo concentrations of both lenalidomide (LEN) and pomalidomide (POM) significantly blunted RANKL upregulation normalizing the RANKL/OPG ratio in human osteoprogenitor cells (PreOBs) when co-cultured with MM cells and also inhibited CCL3 production by MM cells. A reduction in CD49d expression, a molecule critically involved in RANKL upregulation in the MM microenvironment, accompanied this effect. Consistently, the pro-osteoclastogenic property of MM cells co-cultured with PreOBs was reduced by both LEN and POM. We further investigated the effect of these drugs on the transcriptional profile of both MM cells and PreOBs by microarray analysis, which showed that adhesion molecules, such as ITGA8 and ICAM2, are significantly downregulated in MM cells. Our data suggest that LEN and POM inhibit MM-induced OC formation through normalization of the RANKL/OPG ratio targeting the expression of adhesion molecules by MM cells.


Assuntos
Osteoblastos/metabolismo , Osteoprotegerina/genética , Ligante RANK/genética , Talidomida/análogos & derivados , Microambiente Tumoral/efeitos dos fármacos , Antineoplásicos/farmacologia , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Quimiocina CCL3/genética , Quimiocina CCL3/metabolismo , Técnicas de Cocultura , Relação Dose-Resposta a Droga , Citometria de Fluxo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Fatores Imunológicos/farmacologia , Integrina alfa4/genética , Integrina alfa4/metabolismo , Lenalidomida , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Osteoblastos/citologia , Osteoprotegerina/metabolismo , Ligante RANK/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Talidomida/farmacologia , Células Tumorais Cultivadas , Microambiente Tumoral/genética
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